Diabetic kidney disease in pediatric patients: A current review

Abstract

In the last decades, a significant increase in the incidence of diabetic kidney disease (DKD) was observed concomitant with rising diabetes mellitus (DM) incidence. Kidney disease associated with DM in children and adolescents is represented by persistent albuminuria, arterial hypertension, progressive decline in estimated glomerular filtration rate to end-stage renal disease and increased cardiovascular and all-cause morbidity and mortality of these conditions. In medical practice, the common and still the “gold standard” marker for prediction and detection of diabetic kidney involvement in pediatric diabetes is represented by microalbuminuria screening even if it has low specificity to detect early stages of DKD. There are some known limitations in albuminuria value as a predictor biomarker for DKD, as not all diabetic children with microalbuminuria or macroalbuminuria will develop end-stage renal disease. As tubular damage occurs before the glomerular injury, tubular biomarkers are superior to the glomerular ones. Therefore, they may serve for early detection of DKD in both type 1 DM and type 2 DM. Conventional and new biomarkers to identify diabetic children and adolescents at risk of renal complications at an early stage as well as renoprotective strategies are necessary to delay the progression of kidney disease to end-stage kidney disease. New biomarkers and therapeutic strategies are discussed as timely diagnosis and therapy are critical in the pediatric diabetic population.

Key Words: Diabetes, Kidney disease, Biomarkers, Microalbuminuria, Therapy, Children

Core Tip: Several reviews in the literature contributed to the pathophysiology, diagnostics and therapeutic options for diabetic kidney disease in pediatric patients. In this review, we reported the latest data regarding novel biomarkers and methods to identify diabetic children and adolescents at risk of renal complications at an early stage as well as renoprotective strategies to delay the progression of kidney disease to end-stage kidney disease.

INTRODUCTION

Diabetes mellitus (DM), a chronic metabolic condition, is characterized by complete or insufficient insulin production. The main form of DM in childhood and adolescence is type 1 DM (T1DM) compared to type 2 DM (T2DM), which is more frequent in adulthood. Within the last 20 years, DM prevalence increased significantly worldwide. In the last decades, we have also assisted in an ascending trend in the prevalence of T2DM in childhood and youth because of the outbreak in juvenile obesity prevalence[1]. T1DM and T2DM have similar symptoms upon diagnosis, and both include polyuria, polydipsia and polyphagia. While obesity and insulin resistance signs (acanthosis nigricans and polycystic ovarian syndrome) are typical hallmarks of T2DM, loss of weight may be present in both types of DM[1].

Both T1DM and T2DM, with lasting inadequate glycemic control, are associated with long-term vascular complications[2] and a significant increase in mortality, especially in those who develop kidney disease[3]. While DM represents the main worldwide cause of end-stage kidney disease in adults, this is uncommon during childhood[2,3].

Although specific kidney structural changes in DM patients, namely thickening of the glomerular basement membrane and mesangial expansion, appear soon after DM onset (1.5 years to 5.0 years), they are in a clinically silent phase[4]. These structural changes of diabetic kidney injury progress at different rates among T1DM patients, and this is more evident in T2DM cases[4]. Clinical and biological abnormalities (micro/macroalbuminuria) and glomerular filtration rate (GFR) decline will develop over a longer period (10 years to 25 years)[3]. This emphasizes that diabetic kidney disease (DKD) starts early. Therefore, an early diagnosis, intensive monitoring and therapeutic interventions are necessary. Albuminuria and changes in GFR, which are late biomarkers, are the most used tools to assess kidney involvement. Diagnostic strategies for early diagnosis of kidney involvement are necessary.

There are several reviews in the literature that contributed to the pathophysiology, diagnostics and therapeutic options for DKD in pediatric patients. In this work, the state-of-the-art novel biomarkers and methods to identify diabetic children and adolescents at risk of renal complications at an early stage as well as renoprotective strategies to delay the progression of kidney disease to end-stage kidney disease was carried out.

EPIDEMIOLOGY OF DM IN CHILDREN

From 2002 to 2015 the Centers for Disease Control and Prevention reported a 4.8% increase per year for T1DM and a 1.9% increase per year for T1DM in youths aged < 20 years[5]. A very recent study, comprising six areas of the United States from 2001 to 2017, reported an important increase in estimated prevalence for both T1DM and T2DM (T1DM from 1.48 to 2.15 per 1000 youths < 19 years and T2DM from 0.34 to 0.67 per 1000 youths among those aged 10-19 years)[6]. Up-to-date research that included a large cohort of Hungarian children and teenagers during the period 2001 to 2016 (covering 16 years), showed that T1DM is still the most common type, and its prevalence is rising, with a significant male predominance (male/female ratio: 1.25). Also, there is a high prevalence of T2DM, affecting more females every year (female/male ratio: 2.86)[7]. A Danish study showed no increase in T2DM prevalence in children and adolescents[8], while in the United Kingdom a rising incidence and prevalence of T2DM have been observed in youths, especially in some ethnicities[9].

Contributing risk factors to this major increase in incidence are obesity, race, ethnicity, exposure to maternal obesity and diabetes as well as exposure to environmental contaminants[6]. There is an increased morbidity and mortality rate, mainly in T1DM and in those with early T2DM onset. According to Rhodes et al[10], a considerably lower life expectancy (approximately 15 years) was observed in the diabetic group compared to the general population of children without diabetes[10]. A significantly shorter life expectancy was reported in children developing T1DM before 10 years of age (loss of 17.7 years for females vs 14.0 years for males) compared with those diagnosed at 25-30 years (loss of 10.0 years for females and 9.4 years for males)[11]. There is a double cardiovascular risk in pediatric diabetes that triggers early cardiovascular mortality and a four-fold higher mortality rate for all causes in youth[12]. In a nationwide Swedish study of patients with T1DM, age before 10 years at diabetes onset, was the most important risk factor for survival and cardiovascular disease (coronary heart disease and acute myocardial infarction) in their early adult years, especially in females (2-3-fold higher vs males)[13].

DM represents the main cause of end-stage renal disease (ESRD) worldwide in adults[14]. Diabetic nephropathy affects 20% (1 in 5) of adults with diabetes[15]. Within the pediatric population, a significant increase in the incidence of DKD was also observed, the prevalence rate being three times higher in 2013 compared to 2002 (1.16% to 3.44%)[16].

A 4-fold higher risk of kidney failure was found in a large cohort of youth with T2DM vs those with T1DM[17]. Also, compared with the control group, those with youth-onset T2DM had a 16-fold higher risk of a kidney disorder, a 23-fold higher risk of severe renal injury and a 39-fold increased risk of ESRD[17]. A multicenter study reported that more than a quarter (28%) of T2DM youth aged under 20 years developed microalbuminuria[18].

PATHOPHYSIOLOGY

Chronic hyperglycemia leads to the occurrence of diabetic nephropathy, retinopathy and neuropathy as well as macrovascular complications (cardiovascular disease: Stroke, coronary artery disease, peripheral vascular disease)[1,19,20]. DKD recognizes four major pathogenic mechanisms: Glomerular damage, tubular injury, inflammation and oxidative stress[21] (Figure 1). In DKD patients there are important alterations in tubules as well as in the interstitium. These findings may pave the way, or they may appear concomitant with glomerular changes[22].

Figure 1 Pathogenesis in diabetic kidney disease. DKD: Diabetic kidney disease.

This is sustained by tubular hypertrophy observed in the immediate future of hyperglycemia. Also, an increase in tubular basement membrane thickening was found even among diabetic patients with normoalbuminuria. Tubular basement membrane is one of the location of the earliest structural changes. Therefore, it may represent a better severity marker of DKD than glomerular basement membrane alteration[22]. Pathological glomerular changes in DKD are typical and consist of glomerular basement membrane thickening, podocyte foot process widening, expansion of the mesangial matrix and loss of endothelial fenestrations[23].

There is a greater risk for complication occurrence in youths with T2DM vs adults with T1DM and T2DM[1]. The main microvascular complication of diabetes is represented by DKD and later by diabetic nephropathy, which finally leads to ESRD. In time, with diabetes evolution, clinical and biological changes will be observed (Figure 2). DKD, one of the most important and frequent complications of DM, recognizes a wide spectrum of risk factors, some of which are modifiable. Therefore, DKD occurrence or evolution may be considerably influenced by strict control of these factors that are listed in Table 1. Children with T1DM may have damaged renal function at the disease onset as acute complications through acute kidney injury (AKI) and renal tubular damage as well as chronic complications by diabetic nephropathy development[24].

Figure 2 Changes in diabetic kidney disease: Blood pressure evolution and glomerular filtration rate decline along with albuminuria level. Influence of factors involved in diabetic kidney disease occurrence and progression. N: Normal; DKD: Diabetic kidney disease; BP: Blood pressure; GFR: Glomerular filtration rate; LDL-C: Low-density lipoprotein cholesterol; BMI: Body mass index; HbA1c: Glycated hemoglobin.

Table 1 Risk factors for diabetic kidney disease development.

Non-modifiable	Modifiable
Small/young age at DM onset	Poor glycemic control
Diabetes duration	Glucose variability: Hypo/hyperglycemia
Puberty	Overweight/obesity
Family history of diabetic complications and insulin resistance	Dyslipidemia
Genetic factors	High blood pressure
Race/ethnicity	Microalbuminuria
	Smoking, alcohol
	Intrauterine exposure (maternal diabetes, obesity)
	Low birth weight

DM: Diabetes mellitus.

Genetic aspects

DKD is a multifactorial disorder and is influenced by genetic susceptibility, epigenetics and environmental factors (such as lifestyle, diet and medication). Also, oxidative stress, metabolic disturbance, activation of the renin-angiotensin-aldosterone system and production of inflammatory factors are involved in the development and progression of DKD[25]. Genetic and epigenetic studies were performed to understand the pathogenesis of the DKD and to identify genes that confer susceptibility to disease. Genetic studies of DKD investigated mainly the association between genomic DNA variants (for example, single nucleotide polymorphisms, copy number variants, etc) and clinical phenotypes of DKD in both T1DM and T2DM[26]. Epigenetic modifications (histone modifications and DNA methylation) may play a critical role in DKD as it was shown that histone acetylation and methylation are involved in the regulation of inflammation and fibrosis in DKD[27]. Epigenetics studies of DKD investigated the potentially inherited changes in gene expression that occur without changing the DNA nucleotide sequence.

Candidate gene association studies, genome-wide association studies (GWAS) and epigenome-wide association studies were performed in DKD patients[28]. A large meta-analysis study conducted by Mooyaart[29] identified 24 genetic variants in 16 genes (EPO, APOE, APOC1, ACE, ALR2, eNOS, HSPG2, VEGF, FRMD3, GREM1, ELMO1, CCR5 and CNDP1, CARS, UNC13B and CPVL/CHN2), which are the most likely to be associated with diabetic nephropathy[29]. Recently, Tziastoudi et al[30] conducted a systematic review and meta-analysis of genetic association studies in diabetic nephropathy in order to elucidate the contribution of genetic background in the development of this disease and observed an association with the genes revealed by Mooyaart[29] and some additional genes (ACACB, ADIPOQ, AGT, AGTR1, AKR1B1, ATP1B2, ATP2A3, CGNL1, CNDP1, CYGB-PRCD, EDN1, ENPP1, FLT4, FTO, GLO1, HMGA2, IGF2/INS/TH cluster, interleukin genes (IL1B, IL8, IL10), KCNQ1, KNG, LOC101927627, MTHFR, NOS3, SETD7, SIRT1, SLC2A1, SLC2A2, SLC12A3, SLC19A3, TCF7L2, TGFB1, TIMP1, TTC39C, UNC13B, VEGFA, WTAPP1, WWC1, XYLT1)[30].

Genome-wide association studies identified about 30 genes associated with DKD (for example ELMO1, CNDP1, FRMD3, MMP9, UMOD, SLC12A3, etc)[25]. Epigenome-wide association studies identified several genes (for example TRPM6, AQP9, SLC22A12, HP, HYAL2, AGTX) that have epigenetic effects on DKD[25]. The data presented above provide further evidence for the contribution of genetic factors in DKD offering new perspectives in the discovery of new therapies for personalized medicine.

DIAGNOSIS

GFR abnormalities

Hyperfiltration, defined as an increase in GFR with more than 2 standard deviations than the mean GFR value, is related to an early increase in renal blood flow and high intraglomerular pressure[31]. In the first phases of DKD, hyperfiltration is observed in up to 40% of diabetic patients[32]. In both T1DM and T2DM, hyperfiltration has been linked to GFR loss[33,34]. Hyperfiltration was noticed more frequently in females vs males in both T1DM and T2DM[32,35]. The estimated GFR (eGFR) in children and adolescents with T1DM or T2DM should be screened at diagnosis and then annually[36]. These ongoing changes help us to assess DKD stages, which are presented in Table 2[20,21,37]. Normal GFR values according to child age are listed in Table 3.

Table 2 Diabetic kidney disease stages.

Stage	Estimated period	Characteristics	GFR	BP	Biomarker-albuminuria	Biomarker UACR mg/mmoL
1 = hyperfiltration	From diabetes onset to 5 yr	Glomerular hyperfiltration and hypertrophy. No ultrastructure abnormality. A 20% increase in renal size. ↑Renal plasma flow	N/increased	N	Normoalbuminuria < 30 mg/g	< 2
2 = silent	From 2 yr after onset	Mild GBM thickening and interstitial expansion	N	N	Normoalbuminuria < 30 mg/g	< 3
3 = incipient	5–10 yr after onset	More significant changes vs stage 2. Moderate tubular and GBM thickening and variable focal mesangial sclerosis	GFR–N or mild decreased	Increasing BP; +/- hypertension	Microalbuminuria appears Albuminuria 30-300 mg/g	2-20
4 = overt	10-15 yr after onset	Marked GBM thickening and variable focal mesangial sclerosis	GFR-decreased < 60 mL/min/1.73 m2	BP↑	Macroalbuminuria > 300 mg/g	> 20
5 = uremic		Diffuse glomerulosclerosis, ESRD	GFR-marked decreased < 15 mL/min/1.73 m2	BP↑	Decreasing albuminuria

UACR: Urinary albumin to creatinine ratio; GBM: Glomerular basement membrane; GFR: Glomerular filtration rate; BP: Blood pressure; ESRD: End-stage renal disease; ↑: Increase; N: Normal.

Table 3 Normal glomerular filtration rate limit at different ages according to KDOQI Guidelines[66] and Hogg et al[67].

Age	Gender	Normal GFR
1 wk	Males and females	41 ± 15 mL/min/1.73 m2
2–8 wk	Males and females	66 ± 25 mL/min/1.73m2
> 8 wk	Males and females	96 ± 22 mL/min/1.73 m2
2–12 yr	Males and females	133 ± 27 mL/min/1.73 m2
13–21 yr	Males	140 ± 30 mL/min/1.73m2
13–21 yr	Females	126 ± 22 mL/min/1.73m2

GFR: Glomerular filtration rate.

Seric and urinary biomarkers for DKD

Common markers for kidney injury are creatinine, albuminuria, cystatin C, neutrophil gelatinase-associated lipocalin and alfa-1-microglobulin in plasma and urine. Kidney function in pediatrics is assessed mainly by eGFR according to updated/bedside Schwarts equation eGFR = k × height (cm)/serum creatinine (mg/dL), k = 0.413[38].

In a recent study, 11.5% of Romanian children with T1DM had DKD, manifested as transitory microalbuminuria (7.7%) and incipient diabetic nephropathy (3.8%)[39]. In another research study, T1DM patients were found to have microalbuminuria in 30% of cases, representing the most common microvascular complication. In T1DM children the occurrence of microvascular complications was correlated with metabolic control, higher glycated hemoglobin, albuminuria, systolic blood pressure (SBP), triglycerides and total cholesterol[40].

Microvascular as well as macrovascular complications can lead to serious morbidity and mortality. Nephropathy (which is preceded by microalbuminuria), retinopathy and neuropathy represent diabetic microvascular complications[2,41]. According to the International Society for Pediatric and Adolescent Diabetes guidelines, annual microalbuminuria or urinary protein screening should start from the age of 11 years and after 2 years of diabetes evolution and then annually. It was demonstrated that persistent microalbuminuria predicts the progression to ESRD and is linked with an increased risk of macrovascular complications occurrence[41].

In T1DM pediatric patients, urine microalbumin to creatinine ratio (UACR) monitoring should start at puberty or 10 years of age (whichever is earlier), and when the child has had DM for 5 years this parameter should be checked annually. In T2DM the UACR should be checked at diagnosis and every year thereafter[36].

In medical practice, the common and still the “gold standard” marker for prediction and detection of diabetic kidney involvement in pediatric diabetes is represented by the microalbuminuria screening[21], even if it has a low specificity and sensitivity to detect early stages of DKD. Microalbuminuria screening should be done annually by timed overnight or 24-h urine collections (albumin excretion rate) or first-morning UACR[41].

Definitions of albuminuria and its abnormalities are based on the International Society for Pediatric and Adolescent Diabetes Clinical Practice Consensus Guidelines[37,41]. Normoalbuminuria is defined as a urine albumin level of ≤ 30 mg/L in all first-morning urine specimens, while microalbuminuria is characterized by the presence of an albumin limit of 30–300 mg or 20–200 μg/min in 24-h urine collection or a value of 30-300 mg/L in at least 2 of 3 first-morning urine specimens. Another parameter, namely UACR of 2.5–25.0 mg/mmol in males or 3.5–25.0 mg/mmol in females in at least 2 of 3 first-morning urine specimens quantifies microalbuminuria. Macroalbuminuria is defined as the presence of > 300 mg/L albumins in at least two first-morning urine specimens[37,41].

There are some limitations in albuminuria value as a biomarker for the prediction and detection of DKD, as not all diabetic children with micro- or macroalbuminuria will present a decrease in kidney function. Also, there are a lot of factors that may influence albuminuria level, UACR and eGFR: Fever, infection, diet, hydration status, hemodynamics, stress, physical activity, periods and hyperglycemia. Furthermore, a significant proportion of cases with microalbuminuria (up to 40%) may return to normoalbuminuria with strict glycemic and blood pressure (BP) control. Therefore, microalbuminuria can be transitory[21].

Microalbuminuria incidence in children with T1DM spans between 3% to 30%[37]. A cross-sectional study that involved children with T1DM reported a 25.0% frequency for microalbuminuria, while macroalbuminuria was found in 3.5% of these cases. The results of the cited study revealed a significantly higher (3 times) prevalence of microalbuminuria in T2DM (68%) compared to T1DM (24%) patients[37]. This is of particular interest given that children with T1DM are already at risk for renal complications secondary to DKD over the long term. A recent study reported early occurrence of microalbuminuria within 2 years of diagnosis of DM in 3.5% (7 of 199) of patients, whereas in 2 of those with microalbuminuria it appeared within the 1^st year of diagnosis (in 7 mo)[37].

In a recent study, Hursh et al[24] showed that more than 64% of children hospitalized for DKD developed AKI. The same authors showed that a decreased serum bicarbonate level (< 10 mEq/L) and an increased heart rate are associated with a higher risk of severe AKI[24]. Higher morbidity and mortality rate is encountered in diabetic children that developed AKI along with a higher risk of chronic kidney disease, a finding that is particularly important in these patients who are already at risk for DKD[24].

It is already known that patients with DM may present with kidney damage (decrease in GFR) but without micro- or macroalbuminuria[42]. Therefore, other biomarkers that precede albuminuria should be considered more reliable to predict renal lesions, especially in the early stages. However, most of these biomarkers still need validation in clinical practice[43].

As tubular damage occurs before the glomerular injury, tubular biomarkers are superior to the glomerular ones, namely microalbuminuria. Therefore, they may serve for early detection of DKD in both T1DM and T2DM[44]. Tubulointerstitial damage may be suggested by the urinary albumin-to-creatinine to total protein-to-creatinine ratio of 0.40, with high sensitivity and specificity[45].

In patients without glomerular involvement, low-molecular-weight (LMW) proteinuria or non-albumin proteinuria represents an adequate marker of tubular dysfunction[46]. Urinary LMW proteins are absorbed in the proximal tubules so healthy individuals excrete up to 20 mg of LMW proteins/d in urine[46]. Alpha1 microglobulin, beta-2 microglobulins, immunoglobulin light chains, retinol-binding protein, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D-glucosaminidase, kidney injury molecule 1 and liver-type fatty acid-binding protein, etc are included in the LMW protein group[46]. In the early period of diabetes, an increase in urinary tubular biomarkers suggests that kidney injury is present[47].

A recent study showed the association of proximal tubule (alpha-1 microglobulin and kidney injury molecule 1) and podocyte (nephrin, vascular endothelial growth factor) damage biomarkers in T2DM even in the normoalbuminuric stage, indicating they may serve for early DKD diagnosis[47].

Urinary NGAL level increases before the onset of microalbuminuria in the very early phase of the kidney disease[48]. Alongside urinary biomarkers of tubular health (NGAL), the oxidative stress biomarker (pentosidine) may be used in the early detection of diabetic nephropathy before the microalbuminuric phase, as they correlate with albumin excretion and loss of nocturnal dipping of SBP and mean arterial BP[49].

Klotho, a transmembrane protein, is composed of a large extracellular and a small intracellular domain. Klotho is highly expressed in the renal tissue, especially in the distal tubules. The extracellular domain is cleaved by membrane proteases and discharged into the bloodstream, urine and cerebrospinal fluid as soluble klotho (s-klotho)[50,51]. A faster decline in eGFR was observed in DKD patients with low levels of serum s-klotho concentrations[52], which was opposite to the results of another study where s-klotho levels did not correlate with eGFR[50]. Bob et al[50] found a direct correlation of s-klotho levels with the rate of eGFR decline and with the serum levels of tubular injury marker kidney injury molecule 1[50]. A recent study found an inverse correlation between the klotho and glycated hemoglobin levels in T1DM children suggesting its possible role in chronic complications of diabetes occurrence[53].

Early stage prediction and recognition of DKD before microalbuminuria occurrence have a pivotal role in providing timely management. In this process, the assessment of more sensitive and specific biomarkers is essential. A new study showed that serum cystatin C may be used as a biomarker for DKD at an early stage in T1DM children with disease duration not exceeding 5 years before albuminuria detection[21]. The same study found a significantly lower eGFR-cystatin C value in diabetic children compared to controls. Also, significantly higher urinary cyclophilin A (CypA) and urinary CypA/ creatinine ratios were found in T1DM children with microalbuminuria compared to the control group or normoalbuminuric subjects[21].

Salem et al[21] observed a better diagnostic value with the highest sensitivity (93.5%), specificity (71.4%) and accuracy (86.7%) to predict microalbuminuria in T1DM children by the combined use of serum cystatin C and urinary CypA than that of urinary CypA alone[21]. CypA, an endogenous cytosolic protein, is expressed mainly by the proximal tubular epithelial cells. A kidney injury is followed by an increase in urinary CypA concentration[21]. CypA level proved an encouraging biomarker for the early stage of diabetic nephropathy in adults with T2DM, and it correlates with the progression of diabetic nephropathy[54-56]. Novel biomarkers (Table 4) were proposed as early predictors of DKD[21,43].

Table 4 Renal biomarkers of diabetic kidney injury[21,43].

Biomarkers
Traditional biomarkers	Traditional biomarkers of glomerular injury	Albumin/creatinine ratio eGFR	Lack of specificity and sensitivity	(1) Predict the late stages of DKD; (2) Daily variation in urine albumin/creatinine ratio; and (3) eGFR values may be affected by the patient’s hemodynamics, diet and hydration status
Novel biomarkers	Glomerular biomarkers	NF-α, transferrin, Type IV collagen, L-PGDS, IgG, ceruloplasmin, laminin, GAGs, fibronectin, podocalyxin, VEGF	Appear before microalbuminuria	Early predictor of DKD
	Tubular biomarkers	α-1-microglobulin CysC; KIM-1; NGAL; nephrin; NAG; L-FABP; VDBP; CypA; s-Klotho	Appear before/precede microalbuminuria	(1) Are more sensitive vs new glomerular biomarkers; (2) Early predictors of DKD; and (3) Predictor of DKD progression
	Biomarkers of inflammation	Cytokines: TNF-α, IL-1β, IL-18, interferon gamma-IP-10, MCP-1, adiponectin, G-CSF, eotaxins, RANTES or CCL-5, orosomucoid	(1) Precede a significantly increased albuminuria; (2) Correlate positively with albumin excretion rate and intima-media thickness; and (3) May trigger direct renal injury	Predictor of DKD progression
	Biomarkers of oxidative stress	Urinary 8oHdG Pentosidine		Predict the development of DKD

L-PGDS: Lipocalin-type prostaglandin D synthase; IgG: Immunoglobulin G; GAGs: Glycosaminoglycans; CysC: Cystatin C; KIM-1: Kidney injury molecule 1; 8oHdG: 8-oxo-7,8-dihydro-2-deoxyguanosine; RANTES: Regulated on activation, normal T cell expressed and secreted; G-CSF: Granulocyte colony-stimulating factor; MCP-1: Monocyte chemoattractant protein 1; IP-10: Induced protein-10; TNF-α: Tumor necrosis factor α; IL: Interleukin; CypA: Cyclophilin A; VDBP: Vitamin D-binding protein; L-FABP: Liver-type fatty-acid binding protein; NAG: N-acetyl-β-D-glucosaminidase; NGAL: Neutrophil gelatinase-associated lipocalin; DKD: Diabetic kidney disease; eGFR: Estimated glomerular filtration rate; VEGF: Vascular endothelial growth factor; CCL-5: Chemokine ligand 5T.

Urinary biomarkers in DKD are crucial as they can indicate the site of injury within the nephron (structural biomarkers) as well as the loss of/reduced function of the nephron (functional biomarkers) and the main pathophysiological pathways (pathophysiological biomarkers)[57]. The proposed functional and/or structural tubular biomarkers might be valuable in the timely detection of DKD[57].

BP in diabetic children

Another important sign of diabetes-related nephropathy is BP measurement. In pediatric T2DM the guidelines recommend BP and UACR evaluation at diagnosis and annually thereafter[58].

An important and modifiable risk factor for the development of DKD is hypertension[59]. Arterial hypertension is an important and frequent risk factor for the appearance of cardiovascular disease in T1DM patients. High BP triggers the development and progression of microvascular complications, namely nephropathy, and retinopathy.

Ambulatory blood pressure measurement is superior to office BP measurements in predicting future cardiovascular events and targeting organ damage[60]. In their study, Shalaby and Shalaby[60] showed an abnormal BP profile for systolic and diastolic BP, with significant loss of nocturnal dipping. A significantly higher frequency of non-dipping patterns was observed in T1DM patients with microalbuminuria[60].

A recent study that comprises 3529 children and adolescents with T1DM revealed impaired BP regulation with elevated systolic BP, nocturnal diastolic BP, mean arterial pressure and diastolic dipping but lower nocturnal systolic dipping[61]. Lurbe et al[62] showed that an increase in nocturnal SBP precedes microalbuminuria occurrence within T1DM children[62].

The non-dipper pattern for SBD is one of the earliest abnormalities in the BP profile detected for children with T1DM. Also, non-dipping status has been associated with kidney damage (renal morphological changes) and hyperfiltration in adolescents with T1DM[63]. Also, the non-dipping status seems to be an early predictor of later nephropathy[63].

Teenagers with T1DM are at risk for hyperfiltration and higher UACR (urinary albumin-to-creatinine ratio), which are biomarkers for early/ incipient nephropathy[35]. A recent meta-analysis found that almost 25% of T2DM patients have arterial hypertension, the male sex being more frequently affected, and that 1 in 4 or 5 children have albuminuria[58].

Mamilly et al[49] found an increased urinary NGAL/creatinine (a marker of tubular injury) and pentosidine/creatinine (a marker of oxidative stress) in subjects with T1DM compared to controls even in the absence of microalbuminuria[49]. The same study reported a high incidence of abnormal BP dipping, which is important because dipping abnormalities may serve as a predictor for vascular complications, especially kidney injury in diabetic individuals[49]. The same study proved that urine NGAL correlates with loss of nocturnal dipping of SBP[49].

Based on these data, ambulatory blood pressure measurement represents the gold standard to assess BP regulation and should be used in all diabetic patients for timely therapeutic intervention to prevent renal and cardiovascular diabetic complications later in life.

PROPHYLACTIC AND THERAPEUTIC STRATEGIES FOR DKD

The well-known strategies, namely rigorous glycemic control, strict BP control and modulation of obesity, still represent the most important tools to prevent and slow down the progression of diabetic nephropathy/the deterioration of renal function. These therapies proved to be effective mainly by targeting the modifiable risk factors for diabetic nephropathy, which are listed in Table 1.

A recent systematic review confirmed that early high doses of vitamin D supplementation in combination with renin-angiotensin-aldosterone system blockers may slow the onset or progression of DKD[64]. Standard and some novel proposed therapies in early-stage or late-stage development of diabetic nephropathy are presented in Table 5[20,64,65].

Table 5 Common and new therapeutic strategies in diabetic kidney disease.

Therapy	Drug class	Aim	Mechanism of action	DKD result/effect	Dose adjustment to eGFR (mL/min/1.73 m2)
Conventional therapies
Strict glycemic control (Insulin)	-	HbA1c < 7%	(1) Reduces the risk of microalbuminuria; and (2) Reduces progression of microalbuminuria to macroalbuminuria	Delay DKD progression/risk	GFR = 10–50: Reduce the dose to 75%; GFR < 10: Reduce dose to 50%
Dietary protein/phosphate restriction	-	↓High protein intake	(1) Reduces hyperfiltration; and (2) Slows down/delays the loss of function or progression of diabetic nephropathy in T1DM and T2DM	Lower DKD risk	No restriction. CKD stage 3: 100%-140% of the DRI. CKD stage 4-5: 100%-120% of the DRI
Weight loss, increased physical activity	-		(1) Reduces hyperfiltration; and (2) Reduces albuminuria, especially in moderate/severe obesity	Lower DKD risk	No
Antihypertensive therapy	(1) ACEI/ARB/calcium-channel blockers; and (2) ACEI/ARB + calcium-channel blockers	Control of BP	(1) Reduces albuminuria and delays the onset of DN; (2) Prevents progression of DN in microalbuminuric patients; and (3) Reduces the frequency of microalbuminuria in hypertensive normoalbuminuric cases	Delay DKD progression	ARB, calcium channel blockers: No adjustment ACEI: GFR 30-60: Reduce dose to 50%; GFR < 30: Stop
Treatment of Dyslipidaemia	(1) Atorvastatin; (2) Fluvastatin; and (3) Osuvastatin	Reduce LDL-C	Reduce albuminuria in patients with DKD receiving RAAS blockers	Reduces CV disease/risk	No
Psychological Intervention	(1) Family therapy; (2) Cognitive behavioral therapy; (3) Motivational interviewing; (4) Counselling; (5) Mentoring; and (6) Peer support	Reduce depression	Follow lifestyle adjustment regimens and achieve optimal glucose levels	Delay DKD progression	No
Novel therapies
Vitamin D analogues	Paricalcitol. Calcitriol		(1) Ameliorates nephropathy by reducing the albuminuria; and (2) Prevent glomerulosclerosis	Delay DKD progression	No
Vitamin D metabolites			Inhibit RAAS and prevent glomerulosclerosis	Delay DKD progression/risk	No
Uric acid antagonist	Allopurinol	Uric acid antagonist/xanthine oxidase inhibitor	(1) Reduces urinary TGF-β1 in diabetic nephropathy; (2) Reduces albuminuria in T2DM; and (3) Improves endothelial dysfunction	Delay DKD risk/progression	GFR > 50: No adjustment. GFR 30-50: Reduce dose by 50%. GFR < 10: Reduce dose to 30%, longer interval
Renin inhibitor	Aliskiren	Block RAAS cascade	Reduces albuminuria and serves as an antihypertensive in T2DM	Delay DKD progression	No
Endothelin antagonist or I inhibitor ETA receptor antagonist	Atransetan, avosentan, sparsentan (irbesartan + ETA)		(1) Reduces residual albuminuria in type 2 diabetic nephropathy; (2) Reduces proteinuria in T2DM patients and nephropathy; and (3) Significant proteinuria reduction	Delay/slow DKD progression	Yes
MRA Mineralocorticoid Receptor Antagonists	Spironolactone = nonselective MRA. Eplerenone	↑Natriuresis	Reduce albuminuria and blood pressure in patients with DN when added to a RAAS inhibitor	Delay DKD risk/progression	GFR > 50: No dose adjustment. GFR 30-50: Reduce dose to 25%, once daily. GFR < 10: No use
SGLT2 inhibitors	Empagliflozin, canagliflozin	Glucose-lowering	(1) Improves glycaemic control, reduces fasting blood glucose and HbA1c by increasing urinary glucose excretion; and (2) Reduces the reabsorption of sodium	Delay DKD progression, reduces blood pressure	No
GLP-1 agonist	Liraglutide, semaglutide	Stimulates insulin secretion, ↑satiety	Improves glycaemic control	Delay DKD risk/progression	No
	Exenatide, lixisenatide	Stimulates insulin secretion	Improves glycaemic control	Delay DKD risk/progression	Caution in CrCl < 50 mL/min
DDP-4 inhibitors	Linagliptin, saxagliptin, vildagliptin	Glucose-lowering-preserve the glucagon-like peptide effect	Reduce albuminuria in macroalbuminuric T2DM patients	Delay DKD risk/progression	eGFR < 50 mL/min: Reduce dose by 50%; eGFR < 30 mL/min: Reduce dose by 75%
TZD Thiazolidinediones	Rosiglitazone. Pioglitazone	↓Hepatic glucose production activate peroxisome proliferator-activated receptor-γ to increase tissue insulin sensitivity	(1) Reduce albuminuria in macroalbuminuric T2DM patients; and (2) Lower microalbuminuria and proteinuria	Delay DKD risk/progression	No
Aldosterone synthase (CYP11B2) inhibition		Decrease in plasma aldosterone levels		Delay DKD risk/progression	NL
Anti-inflammatory Compounds
CCR2 Antagonists		Emapticap pegol (NOX-E36), CCX-140	Reduces UACR and HbA1c	In T2DM-delay DKD, DN risk/progression	NL
VAP-1 inhibitors	An adhesion molecule for lymphocytes, regulating leukocyte migration into inflamed tissue	ASP-8232	Reduces albuminuria in T2DM in CKD	Delay DKD risk/progression	NL

ETA: Endothelin type A; T2DM: Type 2 diabetes mellitus; DKD: Diabetic kidney disease; UACR: Urine microalbumin to creatinine ratio; HbA1c: Glycated hemoglobin; GFR: Glomerular filtration rate; RAAS: Renin-angiotensin-aldosterone system; eGFR: Estimated glomerular filtration rate; ↓: Decreased; T1DM: Type 1 diabetes mellitus; CKD: Chronic kidney disease; DRI: Dietary reference intake; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin II receptor blocker; BP: Blood pressure; DN: Diabetic nephropathy; LDL-C: Low-density lipoprotein cholesterol; CV: Cardiovascular; TGF-1: Transforming growth factor 1; MRA: Mineralocorticoid receptor antagonists; SGLT-2: Sodium-glucose cotransporter-2; GLP-1: Glucagon-like peptide 1; CrCl: Creatinine clearance; DPP-4: Dipeptidyl peptidase 4; TZD: Thiazolidinediones; NL: Not listed; CCR2: Chemokine receptor 2; VAP-1: Vascular adhesion protein 1.

CONCLUSION

DKD, the most significant and frequent burden of this metabolic disorder, is still discovered late as microalbuminuria is the most used biomarker for predicting kidney involvement. Novel biomarkers are valuable tools in the detection of kidney damage in the early phases as well as reliable predictors for DKD progression. Therefore, effective therapies may be proposed. Early stage prediction and recognition of DKD in children and adolescents before microalbuminuria occurrence have a pivotal role in preventing the development of and/or progression to irreversible kidney damage and to provide timely management and appropriate treatment by using conventional and novel therapies that may slow the onset or progression of DKD.